Critical illnesses are significant public health issues because of adverse outcomes including the high mortality rate and substantial health care costs. Critical illness survivors suffer significant long-term morbidity and mortality. Biologic daa suggests a relationship between vitamin D and important outcomes in critically ill patients. The recently published VITdAL-ICU trial a randomized controlled trial demonstrates that high dose vitamin D supplementation in critically ill patients with severe vitamin D deficiency appears to improve mortality. How vitamin D supplementation impacts critical care outcomes and which patients may benefit from vitamin D supplementation is not clear. We propose to examine the mechanism of protection of vitamin D and identify biologically plausible biomarkers through examination of the pharmacokinetics of high dose vitamin D supplementation and the modification of circulating metabolites with vitamin D supplementation using human blood samples from the completed VITdAL-ICU trial. Morbidity and mortality related to critical illness remain unacceptably high and novel therapeutic approaches to improve outcomes are urgently needed. Vitamin D is an inexpensive and innovative therapy that has significant potential to improve outcomes in critically ill patients with vitamin D deficiency.